The patients with disorders in which lipids are abnormally accumulated in liver, such as non-alcoholic steatohepatitis (NASH), hypernutritive fatty liver, diabetic fatty liver, alcoholic fatty liver, and toxic fatty liver as well as common fatty liver are increasing year by year. Above all, non-alcoholic steatohepatitis (NASH) is particularly acknowledged as a problem, because it exhibits serious symptoms (see non-Patent Reference 1 or 2). Moreover, it has been pointed out that abnormal lipid accumulation in liver causes liver inflammation or fibril formation in liver (liver cirrhosis) and makes shifts to serious disorders such as liver cancer (see non-Patent References 1 to 4), and thus, inhibiting this lipid accumulation is extremely important.
It is believed that various factors including recent lifestyle changes overlap each other and abnormalities in liver energy metabolism are caused and as a consequence, lipid accumulation in liver occurs. Therefore therapeutic modality is not uniform (see non-Patent Reference 5). Although presently, dietary therapy, exercise therapy, pharmacotherapy and the like are tried as remedies for lipid accumulation in liver, these modalities have difficulties in control or continuing implementation. Therefore, therapeutic effects are not always satisfied. Meanwhile, in pharmacotherapy, polyene-phosphatidyl choline preparation is only listed under coverage. As described above, satisfied treatment modality for lipid accumulation in liver has not been established, and thus development of more effective drug for lipid accumulation has been desired.
It is known that SGLT2 inhibitors are drugs which exhibit blood glucose-lowering action by inhibiting sugar reabsorption in kidney, and are useful as drugs for the prevention or treatment of diabetes mellitus (for example, see Patent References 1 to 19). In addition, as to SGLT2 inhibitor, it has been also proposed that concurrent use of T-1095 represented by formula:
and a peroxisome proliferator-activated receptor (hereinafter referred to as PPAR) agonist or a retinoid X receptor (hereinafter referred to as RXR) agonist can suppress the onset of side effects such as fatty liver caused by PPAR agonists or RXR agonists, and therefore the dosage of PPAR agonist or RXR agonist can be reduced (see Patent Reference 20 or 21). However, it has not ever been known that SGLT2 inhibitors exhibit suppressive effects on abnormal accumulation of liver lipids as described in the present invention.
In the treatment of diabetic fatty liver, use of hypoglycemic agents has been studied (see non-Patent Reference 6). However, usefulness of diabetic drugs with blood glucose-lowering actions has been not confirmed, for example, it has been pointed out that tolbutamide does not exhibit suppressive effects on lipid accumulation in liver (see non-Patent Reference 7), and may adversely cause exacerbation of lipid accumulation in liver (see non-Patent Reference 6).
In addition, it has been reported that clofibrate of an antihyperlipidemic agent causes lipid accumulation in liver as a side effect, while it lowers neutral fat or cholesterol in blood (see Patent Reference 22). Furthermore, it has been reported that microsomal triglyceride transfer protein (hereinafter referred to as MTP) inhibitor of an antihyperlipidemic agent causes lipid accumulation in liver, while it lowers neutral fat or cholesterol in blood (see Patent References 23 and 24 and non-Patent References 8 and 9). As described above, in use of these antihyperlipidemic drugs, no correlation is observed in the amount of neutral fat or cholesterol between in blood and in liver, but induction of fatty liver is observed in some cases.    Patent Reference 1: International Publication WO02/28872 pamphlet;    Patent Reference 2: International Publication WO02/44192 pamphlet;    Patent Reference 3: International Publication WO02/53573 pamphlet;    Patent Reference 4: International Publication WO01/16147 pamphlet;    Patent Reference 5: International Publication WO01/68660 pamphlet;    Patent Reference 6: International Publication WO03/11880 pamphlet;    Patent Reference 7: International Publication WO03/00712 pamphlet;    Patent Reference 8: International Publication WO02/068440 pamphlet;    Patent Reference 9: International Publication WO02/68439 pamphlet;    Patent Reference 10: International Publication WO02/64606 pamphlet;    Patent Reference 11: International Publication WO03/80635 pamphlet;    Patent Reference 12: International Publication WO02/88157 pamphlet;    Patent Reference 13: International Publication WO02/36602 pamphlet;    Patent Reference 14: International Publication WO03/20737 pamphlet;    Patent Reference 15: International Publication WO01/74835 pamphlet;    Patent Reference 16: International Publication WO01/74834 pamphlet;    Patent Reference 17: Japanese Patent Publication 2003-012686;    Patent Reference 18: International Publication WO01/27128 pamphlet;    Patent Reference 19: International Publication WO03/99836 pamphlet;    Patent Reference 20: International Publication WO02/080936 pamphlet;    Patent Reference 21: International Publication WO02/080935 pamphlet;    Patent Reference 22: Japanese Patent Publication H8-119860;    Patent Reference 23: Japanese Patent Publication 2002-220345;    Patent Reference 24: International Publication WO03/075232 pamphlet;    Non-patent Reference 1: Hiromasa Ishii, IGAKU NOAYUMI (Journal of Clinical and Experimental Medicine), 2003, Vol. 206, No. 5, pp. 323-325;    Non-patent Reference 2: Naoki Tanaka and one person, KANZO (Acta Hepatologica Japonica), 2002, Vol. 43, No. 12, pp. 539-549;    Non-patent Reference 3: Kazuhiko Koike, IGAKU NOAYUMI (Journal of Clinical and Experimental Medicine), Vol. 206, No. 5, pp. 385-388;    Non-patent Reference 4: Koutaro Uchimura and three persons, RINSHO TO KENKYU (The Japanese Journal of Clinical and Experimental Medicine), 2003, Vol. 80, No. 3, pp. 503-506;    Non-patent Reference 5: Kenichiro Iwamura, KANZO (Acta Hepatologica Japonica), 1971, Vol. 12, No. 12, pp. 659-669;    Non-patent Reference 6: Kenichiro Iwamura, SAISIN-IGAKU (The Medical Frontline), 1978, Vol. 33, No. 3, pp. 524-531;    Non-Patent Reference 7: A. Beringer and three persons, Deutsche Medizinische Wochenschrift, 1967, vol. 92, No., pp. 2388-2392;    Non-patent Reference 8: Ken Ohashi, Annual review. NAIBUNPI, TAISHA 2000 (Internal Secretion, Metabolism 2000), Chugaiigaku Co. publication, pp. 17-23;    Non-Patent Reference 9: Junichi Osuga, NAIKA (Internal Medicine), 2002, vol. 89, No. 5, pp. 875-881.